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Show ORIGINAL CONTRIBUTION Choroidal and Optic Nerve Infarction in Hepatitis C- Associated Polyarteritis Nodosa Yanina Kostina- 0 ' Neil, MD, Guy V. Jirawuthiworavong, MD, MA, David N. Podell, MD, PhD, and Robert L. Lesser, MD Abstract: A 39- year- old man presented with headache, weight loss, bilateral subdural hematomas, pansinusitis, and visual loss. The neuro- ophthalmologic examination disclosed deep choroidal lesions and bilateral optic disc edema. Orchiectomy for testicular torsion showed acute vasculitis consistent with polyarteritis nodosa ( PAN). Polymerase chain reaction ( PCR) testing revealed hepatitis C. This is the first reported case of PAN due to hepatitis C with early findings of choroidal and optic nerve infarction. (/ Neuro- Ophthalmol 2007; 27: 184- 188) Polyarteritis nodosa ( PAN) is a vasculitis that affects small- to medium- sized vessels, causing a segmental inflammation and necrosis of arteries ( 1- 3). Systemic manifestations include constitutional symptoms ( 70%), peripheral neuropathy ( 65%), arthralgias/ myalgias ( 50%), skin lesions ( 50%) ( most commonly livedo reticularis), renal damage ( 50%), gastrointestinal symptoms ( 40%), hypertension ( 25%), respiratory manifestations ( 25%), central nervous system disease ( 20%), orchitis ( 20%), coronary artery involvement ( 10%), and ear, nose, and throat manifestations ( 7%) ( 3- 5). In PAN, 10%- 20% of patients have ophthalmic manifestations, of which choroidopathy is the most common ( 4,6). Other findings include peripheral ulcerative keratitis, episcleritis, uveitis, necrotizing scleritis, hypertensive retinopathy, occlusive retinal artery disease, Departments of Ophthalmology and Visual Science ( YK- O, RLL) and Medicine ( DNP), Yale University School of Medicine, New Haven, Connecticut; Ocular Immunology and Uveitis ( GVJ), National Eye Institute, National Institutes of Health, Bethesda, Maryland; and Department of Medicine, Waterbury Hospital Health Center, Waterbury, Connecticut. This case was presented at the Walsh Meeting/ North American Neuro- Ophthalmology Society 2002, Copper Mountain, CO. Address correspondence to Yanina Kostina- O'Neil, MD, The Eye Care Group, EC, 40 Temple Street, Suite 5- B, New Haven, CT 06510; E- mail: yko stina@ theeyecaregroup . com nonrhegmatogenous retinal detachment due to choroidal ischemia, anterior or posterior ischemic optic neuropathy, proptosis, cranial nerve paresis, cortical involvement with visual field defects, and orbital apex syndrome ( 4). We report what we believe to be the first case of hepatitis C- associated PAN in which choroidal and optic nerve infarction were recognized before the diagnosis of PAN was made. CASE REPORT A 39- year- old Caucasian man developed severe headache, difficulty reading, photophobia, and unsteady gait. Over the past 6 months, he had had nasal congestion and an unexplained 20- 30 pound weight loss with night sweats. He was a heavy smoker, denied intravenous drug use, and had multiple sex partners and tattoos. There was no history of connective tissue disease. White blood count was 27.9 X 103JULL , hemoglobin was 12.2 g/ dL, hematocrit was 42.5%, platelet count was 509 X 103| JLL, and the creatinine level was 0.6 mg/ dL. Results of an electrocardiogram ( ECG) were normal. Neurologic examination showed ataxia and impairment of fine movements of the right hand. Brain MRI showed pansinusitis and bilateral subdural hematomas with a 4 mm midline shift ( Fig. 1). Brain MRA was negative. The left subdural hematoma was evacuated. Postoperatively, the brain CT scan showed a decrease in the size of the left subdural hematoma. Shortly thereafter, he reported a 1- month history of epistaxis, pain in the right periocular region and base of the skull, and a decline in vision such that he could barely read the headline of a newspaper. Results for repeat brain MRI were unchanged. Three weeks later, a neuro- ophthalmologic examination disclosed best- corrected visual acuities of 20/ 60 in the right eye and 20/ 20 in the left eye. Pupils were normal in size and reactivity without an afferent pupillary defect. There was mild injection of the conjunctiva bilaterally and 1+ cell in the anterior chamber of the right eye. Intraocular pressures were normal. Automated perimetry revealed visual field defects most marked temporally and greater in the right eye than in the left eye ( Fig. 2). 184 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Polyarteritis Nodosa J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 }'.' ~/ v J f- FIC. 1. Postcontrast T1 axial MRI shows bilateral subdural hematomas ( arrows). Ophthalmoscopy revealed bilateral optic disc edema with flame- shaped hemorrhages. Multiple deep, well-circumscribed, white choroidal lesions were present in the posterior poles of both eyes ( Fig. 3) Fluorescein angiography showed optic disc leakage and well- circumscribed choroidal areas of late staining. Brain MRI with venography ( MRV), performed because the optic disc might have signaled increased intracranial pressure, showed no sign of dural sinus thrombosis. The patient was treated with clarithromycin for pansinusitis. A further workup revealed the following: alanine aminotransferase ( ALT), 229 U/ L; aspartate FIG. 2. Visual field examination performed 3 weeks after the patient reported acute binocular visual loss. They show enlarged blind spots and nerve fiber bundle defects. aminotransferase ( AST), 136 U/ L; alkaline phosphatase, 241 U/ L; albumin, 3.0 g/ dL; erythrocyte sedimentation rate ( ESR), 85 mm/ h; RF, 90 ( normal 0- 39); positive urine protein; and normal titers for HIV, cytomegalovirus ( CMV), toxoplasmosis, and histoplasmosis. Results of tests for Lyme disease, antiphospholipid antibodies, perinuclear ( P)- antineutrophilic cytoplasmic antibodies ( ANCAs) (< 1: 40) and cytoplasmic ( C)- ANCAs (< 1: 40), purified protein derivative ( PPD), reactive plasma protein ( RPR), fluorescent treponema antibodies- absorbed ( FTA- ABS), aspergil-lus antigen, and complement 3 ( C3), and complement 4 ( C4) were also normal or negative as were a chest x- ray and blood cultures. The patient was scheduled for a sinus biopsy, but 2 days before the biopsy, he developed severe groin pain. A urologist diagnosed testicular torsion and acute epididymitis. After emergency unilateral orchiectomy, pathologic FIG. 3. Fundus photography was performed 3 weeks after the patient reported acute binocular visual loss. It shows optic disc edema and choroidal lesions in both eyes. 185 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Kostina- O'Neil et al FIG. 4. Histopathology of the testis and epididymis. A. Low magnification shows acute vasculitis with fibrinoid necrosis of small- and medium- sized arteries ( arrow) consistent with PAN. B. Similar findings are demonstrated under high magnification. No granulomatous features were identified. examination showed acute vasculitis of medium- sized arteries without evidence of granulomas. The findings were considered consistent with a diagnosis of PAN ( Fig. 4). Ten days later, visual acuity decreased to 20/ 300 in the right eye and to 20/ 40 in the left eye. Ophthalmologic examination disclosed diffuse bilateral scleritis and anterior nongranulomatous uveitis in the right eye. The choroidal lesions were larger and coalescing ( Fig. 5). Treatment was begun immediately with 1 g intravenous methylprednisolone for 1 day followed by 60 mg prednisone/ day and 81 mg aspirin/ day Two days later, the patient developed mild substernal and left axillary chest pain. An ECG showed a myocardial infarction; cardiac catheterization showed occlusion of the left circumflex artery. The posterior descending artery and left ascending artery had imaging changes consistent with vasculitis. The FIG. 5. Fundus photography of the right eye performed several weeks after that presented in Figure 3. It shows enlargement of the choroidal lesions. patient was treated with 60 mg prednisone daily, 50 mg cyclophosphamide 3 times per day, 3 million units alfa- 2b interferon 3 times per week subcutaneously, and 600 mg ribavirin twice per day. Subsequently, a polymerase chain reaction ( PCR) test confirmed that the patient was hepatitis C- positive with a viral load of > 1 million copies. Results of cryoglobulin testing were negative. Hepatitis C- related systemic necrotizing vasculitis consistent with PAN was diagnosed. The result of a repeat P- ANCA measurement was 1: 80 ( negative < 1: 40). The scleritis and iritis improved. Three weeks after initiation of therapy, the choroidal lesions significantly diminished in size and eventually disappeared. Visual acuity improved to 20/ 50 in the right eye and 20/ 20 in the left eye. Three months after systemic treatment, ophthalmoscopy disclosed subretinal fibrosis, atrophy of the retinal pigment epithelium ( RPE), and temporal pallor of the optic disc in the right eye. In the left eye, there was atrophy of the RPE and optic disc pallor ( Fig. 6). Six months after treatment, he developed a juxtafoveal choroidal neovascular membrane in the right eye that was treated with a photodynamic laser. After 12 months of therapy, cyclophosphamide was discontinued, and the patient remained in remission with visual acuities of 20/ 100 in the right eye and 20/ 20 in the left eye. Seven years after the initial illness, visual acuity in the right eye dropped to finger counting due to further RPE atrophy. The visual field in the right eye showed residual paracentral and cecocentral field loss; the visual field in the left eye showed minimal paracentral depression ( Fig. 7). DISCUSSION Our patient presented with prominent choroidopathy and optic neuropathy as early signs of hepatitis C- associated PAN. These features are similar to those reported by Hsu et al ( 7), who described a 70- year- old woman with PAN 186 © 2007 Lippincott Williams & Wilkins Polyarteritis Nodosa J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 FIG. 6. Fundus photography performed 3 months after treatment of PAN. It shows chorioretinal atrophy in the right eye and bilateral optic disc pallor. lesions in the posterior pole and usually has a good prognosis with relatively fast recovery with or without systemic therapy ( 8). Hsu et al ( 9) reported a patient who presented with AMPPE and had vasculitis with features of Wegener granulomatosis and atypical PAN. Pinto Ferreira et al ( 10) reported a patient with PAN whose lesions resembled AMPPE in one eye and serpiginous choroidopathy in the other eye. AMPPE has been reported with cerebral vasculitis ( 11) and meningoencephalitis ( 12). Although Gass ( 8) proposed that the disease process was at the level of the RPE, recent imaging and pathology reports have shown that the underlying problem is in the choroid ( 13). Newman et al ( 14) reported a case of recurrent monocular peripheral visual field constriction sparing acuity in a patient with PAN. Pathologic examination of the orbital and ocular vessels at autopsy showed vasculitis of the short posterior ciliary and small- and medium- sized orbital arteries but not the ophthalmic and central retinal arteries. The authors attributed the episodes of transient peripheral visual loss to intermittent choroidal vascular ischemia. Our patient is also unusual in having hepatitis C. Chronic hepatitis C virus ( HCV) infection is associated with small vessel vasculitis [ mixed cryoglobulinemia ( MC)] or medium- size vessel vasculitis ( PAN). Anti- HCV antibodies are found in 60%- 80% of patients with MC but only in 5%- 12% of patients with PAN ( 15). Other extrahepatic systemic manifestations of hepatitis C include palpable purpura, porphyria cutanea tarda, Mooren corneal ulcer, sicca syndrome, uveitis, B- cell lymphoma, and glomerulonephritis ( 16). The diagnosis of hepatitis C is made by testing for anti- HCV using an enzyme immunoassay ( EIA). Testing for HCV RNA using a sensitive assay such as PCR or transcription- mediated amplification ( TMA) is the most effective method to confirm HCV infection. Although results of liver function tests can be normal, the presence of unassociated with hepatitis C who presented with a central retinal artery occlusion in the right eye and anterior ischemic optic neuropathy with choroidal infarction in the left eye. The single area of choroidal infarction was triangular in shape and was referred to as " the triangular sign of Amalric." In contrast to the case of Hsu et al ( 7), the choroidal lesions in our patient were round, bilateral, distinct, multiple, and small, similar to those in acute multifocal placoid pigment epitheliopathy ( AMPPE). In our patient, the lesions resolved in about 4 weeks, leaving areas of RPE atrophy. The ophthalmic findings in our patient do indeed resemble those of AMPPE, a self- limited condition that presents with multiple yellow- white placoid subretinal ' • : • ' • • ' • • I • • * I • ••• • a • :: & • £ • • • • • I I • • n » ation SK • • • • • • • • • &. - » • • • • • g 8 • • 8 - - FIG. 7. Visual field measurements performed 7 years after treatment of PAN. They show residual paracentral and cecocentral field loss. 187 J Neuro- Ophthalmol, Vol. 27, No. 3, 2007 Kostina- O'Neil et al HCV- RNA in serum indicates active infection ( 15,17). Risk factors for hepatitis C include intravenous drug use and blood transfusions received before 1987. Hepatitis C is treated with pegylated interferon in combination with ribavirin. For untreated PAN, the aggregate 1- year survival rate is 50%, and the 5- year survival rate is 13% ( 18- 21). Major causes of death include mesenteric, renal, cardiac, or cerebral infarction ( 3). Complications may occur in clinically inactive disease when scarring of inflamed vessels causes narrowing of the vascular lumen. Treatment for PAN includes corticosteroids and immunosuppressive agents such as cyclophosphamide and azathioprine. Although the 5- year survival rate improves to 50% with corticosteroid treatment alone, it is as high as 80% with a combination regimen that consists of corticosteroid and cyclophosphamide. ( 22) If treatment is started early, preservation of tissue function is more likely ( 1- 3), hence the need for early recognition of the connection between PAN and the ophthalmic signs demonstrated in our patient. REFERENCES 1. Guillevin L, Lhote F, Gherardi R. Polyarteritis nodosa, microscopic polyangiitis, and Churg- Strauss syndrome: clinical aspects, neurologic manifestations, and treatment. Neurol Clin 1997; 15: 865- 86. 2. Segelmark M, Selga D. The challenge of managing patients with polyarteritis nodosa. Curr Opin Rheumatol 2007; 19: 33- 8. 3. Bonsib SM. Polyarteritis nodosa. Semin Diagn Pathol 2001; 18: 14- 23. 4. Galetta SL. Vasculitis. In: Miller NR, Newman NJ, Biousse V, et al., eds. Walsh andHoyt's ClinicalNeuro- Ophthalmology. Vol 2. 6th ed. Philadelphia: Lippincott, Williams & Wilkins; 2005: 2339^ 5. 5. Kastner D, Gaffney M, Tak T. Polyarteritis nodosa and myocardial infarction. Can J Cardiol 2000; 16: 515- 8. 6. Goldsmith J. 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